This invention relates to novel amide derivatives, processes for preparing them, pharmaceutics containing them and their use as medicines, especially in the treatment of various diseases of the respiratory, urinary and digestive systems.
Antagonism to muscarinic receptors are known to cause bronchodilation, gastrointestinal hypanakinesis, gastric hyposecretion, dry mouth, mydriasis, suppression of bladder contraction, hypohidrosis, tachycardia and the like [cf. Basic and Clinical Pharmacology, 4th ed., APPLETON and LANGE, pp. 83-92 (1989) and Drug News and Perspective, 5(6), pp. 345-352 (1992)].
It has recently been made clear that there are at least three subtypes of muscarinic receptors; M1 receptors being present mainly in the brain; M2 receptors, mainly in the heart, and M3 receptors, on smooth muscles and glandular tissues. Whereas, all of the large number of compounds heretofore known to exhibit antagonism to muscarinic receptors non-selectively antagonize the three subtypes of muscarinic receptors. Consequently, attempts to use these compounds as therapeutic or prophylactic agents for diseases of the respiratory system have caused undesirable side effects such as dry mouth, nausea and mydriasis. Still in addition, particularly serious side effects associated with the central nervous system, such as dementia, attributable to M1 receptors and those associated with the heart, such as tachycardia mediated by M2 receptors pose problems and their solution has been strongly in demand.
An object of the present invention is to provide treating agents of diseases associated with muscarinic M3 receptors, said agents exhibiting highly selective antagonism to muscarinic M3 receptors and little side effects, and being safe and effective.
We have discovered that those compounds which are represented by the following general formula [I]
[in which A stands for a group of the following formula [a0] or [b0]
Ar1, Ar2 and Ar3 each independently stands for optionally substituted phenyl, the substituent being selected from the group consisting of halogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, carbamoyl, lower alkylcarbamoyl and di-lower alkylcarbamoyl; k means 0 or 1; m, n and s each independently means 0, 1 or 2; R1 stands for hydrogen or optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl; R2, R3, R4 and R5 each independently stands for hydrogen or optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl, or R2 and R3, or R4 and R5, may together stand for, independently of each other, optionally substituted trimethylene, propenylene, tetramethylene or 2-butenylene group, the substituent being selected from the group consisting of oxo, hydroxyl, amino, lower alkoxy, lower alkanoyloxy, lower alkylamino, di-lower alkylamino, (imino-lower alkyl)amino, lower alkanoylamino, lower alkoxycarbonylamino, (lower alkylcarbamoyl)amino, lower alkylsulfonylamino, guanidino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, imidazolyl and a group represented by xe2x80x94R7, R7 standing for optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxycarbonyl and imidazolyl; R60 stands for hydrogen, C1-C10 alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl; R61 and R71 each independently stands for C1-C10 alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl, or R61 and R71 may together stand for optionally substituted trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-epoxytetramethylene group, the substituent being selected from the group consisting of oxo, hydroxyl, lower alkyl and lower alkoxy; X stands for carbonyl or methylene; Y stands for nitrogen or methine; and Qxe2x88x92 stands for anion]
exhibit highly selective antagonism to muscarinic M3 receptors, little side effect and high safety, and are very useful for treating various diseases which are associated with muscarinic M3 receptors, e.g., such respiratory diseases as chronic obstructive pulmonary diseases, chronic bronchitis, asthma, chronic respiratory tract obstruction, fibroid lung, pulmonary emphysema and rhinitis; digestive diseases such as irritable bowel syndrome, convulsive colitis, gastroduodental ulcer, convulsion or hyperanakinesia of digestive tract, diverticulitis and pain accompanying contraction of smooth muscles of the digestive system; urinary diseases accompanied by dysuria like urinary incontinence, urgency and pollakiuria in nervous pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystisis; and motion sickness; and have completed the present invention.
The present invention relates to the compounds represented by above general formula [I] or salts thereof, processes for their preparation and their use.
Hereafter the invention is explained in further details, in which the terms used mean the following.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine and iodine atoms.
xe2x80x9cLower alkyxe2x80x9d means C1-C6 linear or branched alkyl groups, examples of which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl groups.
xe2x80x9cLower alkenylxe2x80x9d means C2-C6 linear or branched alkenyl groups, examples of which include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl, 1-butenyl, 1-methyl-2-propenyl, 1 methyl-1-propenyl, 1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 3-methyl-2-butenyl and 4-pentenyl groups.
xe2x80x9cLower alkoxyxe2x80x9d means C1-C6 linear or branched alkoxy groups, examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and isohexyloxy groups.
xe2x80x9cLower alkylcarbamoylxe2x80x9d means carbamoyl groups which are mono-substituted with said lower alkyl groups, examples of which include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl butylcarbamoyl, sec-butylcarbamoyl and tert-butylcarbamoyl groups.
xe2x80x9cDi-lower alkylcarbamoylxe2x80x9d means carbamoyl groups which are di-substituted with said lower alkyl groups, examples of which include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, dipropylcarbamoyl, methylpropylcarbamoyl and di-isopropylcarbamoyl groups.
xe2x80x9cLower alkylaminoxe2x80x9d means amino groups which are mono-substituted with said lower alkyl groups, examples of which include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and tert-butylamino groups.
xe2x80x9cDi-lower alkylaminoxe2x80x9d means amino groups which are di-substituted with said lower alkyl groups, examples of which include dimethylamino, diethylamino, ethylmethylamino, dipropylamino, methylpropylamino and di-isopropylamino groups.
xe2x80x9cImino-lower alkylxe2x80x9d means said lower alkyl groups which are mono-substituted with imino group, examples of which include formimidoyl, acetimidoyl, propanimidoyl, butanimidoyl, pentanimidoyl and hexanimidoyl groups.
xe2x80x9c(Imino-lower alkyl) aminoxe2x80x9d means amino groups which are mono-substituted with said imino-lower alkyl groups, examples of which include formimidoylamino, acetimidoylamino, propanimidoylamino, butanimidoylamino, pentanimidoylamino and hexanimidoylamino groups.
xe2x80x9cLower alkanoyxe2x80x9d means C1-C6 linear or branched alkanoyl groups, examples of which include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl groups.
xe2x80x9cLower alkanoyloxyxe2x80x9d means alkanoyloxy groups having said lower alkanoyl groups, examples of which include acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy and pivaloyloxy groups.
xe2x80x9cLower alkanoylaminoxe2x80x9d means amino groups which are mono-substituted with said lower alkanoyl groups, examples of which include formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino and pivaloylamino groups.
xe2x80x9c(Lower alkylcarbamoyl) aminoxe2x80x9d means amino groups which are mono-substituted with said lower alkylcarbamoyl groups, examples of which include (methylcarbamoyl) amino, (ethylcarbamoyl)amino, (propylcarbamoyl)amino, (isopropylcarbamoyl)amino, (butylcarbamoyl)amino, (sec-butylcarbamoyl)amino and (tert-butylcarbamoyl)amino groups.
xe2x80x9cLower alkylsulfonylxe2x80x9d means alkylsulfonyl groups having said lower alkyl groups, examples of which include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl groups.
xe2x80x9cLower alkylsulfonylaminoxe2x80x9d means amino groups which are mono-substituted with said lower alkylsulfonyl groups, examples of which include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, sec-butylsulfonylamino and tert-butylsulfonylamino groups.
xe2x80x9cLower alkoxycarbonylxe2x80x9d means alkoxycarbonyl groups having said lower alkoxy groups, examples of which include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and pentyloxycarbonyl groups.
xe2x80x9cLower alkoxycarbonylaminoxe2x80x9d means amino groups which are mono-substituted with said lower alkoxycarbonyl groups, examples of which include methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylamino, butoxycarbonylamino, isobutoxycarbonylamino, tert-butoxycarbonylamino and pentyloxycarbonylamino groups.
xe2x80x9cC1-C10 alkyxe2x80x9d means C1-C10 linear or branched alkyl groups, examples of which includes, besides those earlier exemplified lower alkyl groups, 2-methylbutyl, 2-ethylbutyl, 2-methylpentyl, heptyl, octyl, nonyl and decyl groups.
xe2x80x9cCycloalkylxe2x80x9d means C3-C10 cycloalkyl groups, examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl groups.
xe2x80x9cCycloalkyl-lower alkylxe2x80x9d means said lower alkyl groups having above cycloalkyl groups, examples of which include cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl; 2-cyclohexylethyl, cycloheptylmethyl and cyclooctylmethyl groups.
xe2x80x9cCycloalkyl-lower alkyl whose ring portion may be substituted with lower alkylxe2x80x9d means either above cycloalkyl-lower alkyl groups or said cycloalkyl-lower alkyl groups having one, two or more, preferably one or two same or different, earlier named lower alkyl groups at the optional, substitutable position or positions on the cycloalkyl group, examples of which include, besides above-exemplified cycloalkyl-lower alkyl groups, 1-(1-methylcyclopropyl)ethyl, 2-(1-methylcyclopropyl)ethyl, (2,2-dimethylcyclopentyl)methyl, 1-(2,2-dimethylcyclopentyl)ethyl and 2-(2,2-dimethylcyclopentyl)ethyl groups.
xe2x80x9cCycloalkenylxe2x80x9d means C3-C10 cycloalkenyl groups, examples of which include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl and cyclodecenyl groups.
xe2x80x9cCycloalkenyl-lower alkylxe2x80x9d means said lower alkyl groups having said cycloalkenyl groups, examples of which include cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, cycloheptenylmethyl, cyclooctenylmethyl, cyclononenylmethyl and cyclodecenylmethyl groups.
xe2x80x9cAralkylxe2x80x9d means said lower alkyl groups having aryl groups such as phenyl, naphthyl or anthryl, examples of which include benzyl, 1-phenylethyl, 2-phenylethyl, 1-naphthylmethyl and 2-naphthylmethyl groups.
xe2x80x9cAnionxe2x80x9d means those forming a pair with ammonium ions on the compounds of the present invention, which electrically neutralize said compounds. While they are not subject to particular limitations so long as they are pharmaceutically acceptable, anions formed from halogen atoms, inorganic acids, organic sulfonic acids, carboxylic acids and the like, such as 
may be named as examples.
xe2x80x9cSaltsxe2x80x9d of the compounds represented by the general formula [I] means, for example, those pharmaceutically acceptable and customarily used salts of the compounds whose A is expressed by the formula [a0], referring to the general formula [I]. As examples of such salts, acid addition salts at the positions of basic nitrogen atom may be named.
Examples of the acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and perchlorate; organic acid salts such as maleate, fumarate, tartarate, citrate, ascorbate and trifluoroacetate; and sulfonic acid salts such as methanesulfonate, isethionate, benzenesulfonate and p-toluene-sulfonate.
xe2x80x9cTreating agentxe2x80x9d means medicines which are used for treatment and/or prophylaxis of various diseases.
The compounds of the present invention in occasions have stereoisomers such as optical isomers, diastereoisomers or geometrical isomers, depending on the form of the substituents therein. The compounds of the present invention cover all of those stereoisomers and their mixtures.
For more specific disclosures of the compounds of the present invention which are represented by the general formula [I], the symbols used in said formula [I] are explained in further details in the following, citing their preferred specific examples.
A stands for a group of the following formula [a0] or [b0]
R60 stands for hydrogen, C1-C10 alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl.
Examples of C1-C10 alkyl groups as R60 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl, heptyl, octyl and decyl.
Preferred examples of lower alkenyl group as R60 include 2-propenyl and 3-butenyl.
Preferred examples of cycloalkyl group as R60 include cyclopentyl and cyclohexyl.
Preferred examples of cycloalkyl-lower alkyl group whose ring portion may be substituted with lower alkyl as R60 include cyclopropylmethyl, cyclobutylmethyl, 2-(1-methylcyclopropyl)ethyl, cyclopentylmethyl, (2,2-dimethylcyclopentyl)methyl, 1-cyclopentylethyl, cyclohexylmethyl and 1-cyclohexylethyl.
Preferred examples of cycloalkenyl-lower alkyl group as R60 include cycloheptenyl and cyclononenyl.
Preferred examples of aralkyl group as R60 include benzyl.
Preferred examples of R60 include hydrogen, C1-C10 alkyl, cycloalkyl and cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl.
R61 and R71 each independently stands for C1-C10 alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl; or R61 and R71 may together stand for optionally substituted trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-epoxytetramethylene group, the substituent being selected from the group consisting of oxo, hydroxyl, lower alkyl and lower alkoxy.
Preferred examples of C1-C10 alkyl groups as R61 and R71 include C1-C6 alkyl, in particular, methyl, ethyl, propyl and 2-methylbutyl.
Preferred examples of lower alkenyl as R61 and R71 include 2-propenyl and 3-butenyl.
Preferred example of cycloalkyl as R61 and R71 is cyclohexyl.
Preferred examples of cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl as R61 and R71 include cyclopropylmethyl, cyclohexylmethyl, cycloheptylmethyl and cyclooctylmethyl, in particular, cyclopropylmethyl and cyclohexylmethyl, inter alia, cyclopropylmethyl.
Preferred examples of cycloalkenyl-lower alkyl as R61 and R71 include cycloheptenylmethyl and cyclononenylmethyl.
Preferred examples of aralkyl as R61 and R71 include benzyl.
xe2x80x9cOptionally substituted trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-epoxytetramethylene group, the substituent being selected from the group consisting of oxo, hydroxyl, lower alkyl and lower alkoxyxe2x80x9d means unsubstituted trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-expoxytetramethylene; or those having one, two or more, preferably one or two substituents which may be same or different, which are selected from the group consisting of oxo, hydroxyl, lower alkyl and lower alkoxy, at optional substitutable position or positions.
Preferred examples of lower alkyl serviceable as the above substituent include methyl, ethyl and propyl, in particular, methyl.
Preferred examples of lower alkoxy serviceable as the above substituent include methoxy and ethoxy.
Preferred examples of the above substituents include lower alkyl groups.
Among the trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-epoxytetramethylene groups, for example, tetramethylene, 2-butenylene, pentamethylene or 2,3-epoxytetramethylene are preferred.
Hence, among the optionally substituted trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-epoxytetramethylene represented jointly by R61 and R71, those preferred include unsubstituted tetramethylene, 2-butenylene, pentamethylene and 2,3-epoxytetramethylene; and lower alkyl-substituted tetramethylene, 2-butenylene, pentamethylene and 2,3-epoxytetramethylene.
Preferred embodiments of R61 and R71 include: those wherein R61 and R71 each independently is selected from C1-C10 alkyl, lower alkenyl or cycloalkyl-lower alkyl; or R61 and R71 together stand for trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-epoxytetramethylene which optionally have substituent(s) selected from the group consisting of oxo, hydroxyl, lower alkyl and lower alkoxy. More specifically, the preferred embodiments include those wherein both R61 and R71 are methyl ethyl, propyl, 2-propenyl or cyclopropylmethyl; R61 is cyclohexylmethyl and R71 is methyl; or R61 and R71 together form tetramethylene, 2-butenylene, pentamethylene or 2,3-epoxytetramethylene group.
As Qxe2x88x92, for example, anions formed from halogen atoms such as Clxe2x88x92, Brxe2x88x92 and Ixe2x88x92 are preferred;
s means 0, 1 or 2; and Qxe2x88x92 stands for anion, convenient s being 1.
Ar1, Ar2 and Ar3 each independently stands for optionally substituted phenyl, the substituent being selected from the group consisting of halogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, carbamoyl, lower alkylcarbamoyl and di-lower alkylcarbamoyl.
Said xe2x80x9coptionally substituted phenyl, the substituent being selected from the group consisting of halogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, carbamoyl, lower alkylcarbamoyl and di-lower alkylcarbamoylxe2x80x9d mean unsubstituted phenyl or phenyl having substituent(s) at substitutable, optional position(s), said one, two or more, preferably one or two same or different substituents being selected from the group consisting of halogen, hydroxyl, lower alkyl, lower alkenyl, lower alkoxy, carbamoyl, lower alkylcarbamoyl and di-lower alkylcarbamoyl.
Among the halogen atoms as the substituent, for example, fluorine, chlorine and bromine, inter alia, fluorine, are preferred.
Among the lower alkyl groups as the substituent, for example, methyl, ethyl and propyl are preferred.
Among the lower alkenyl groups as the substituent, for example, vinyl, 1-propenyl and 2-propenyl are preferred.
Among the lower alkoxy groups as the substituent, for example, methoxy and ethoxy are preferred.
Among the lower alkylcarbamoyl groups as the substituent, for example, methylcarbamoyl and ethylcarbamoyl are preferred.
Among the di-lower alkylcarbamoyl groups as the substituent, for example, dimethylcarbamoyl and diethylcarbamoyl are preferred.
As the substituent, halogen atoms and lower alkyl groups are preferred.
As Ar1, Ar2 and Ar3, independently of each other, phenyl which is optionally substituted with halogen or lower alkyl are preferred. In particular, such cases wherein all of them are unsubstituted phenyl, or phenyl substituted with halogen, inter alia, fluorine, are preferred.
The suffix k stands for 0 or 1; and m and n, each independently, 0, 1 or 2, preferred n being 1 or 2.
R1 stands for hydrogen or optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl.
Said xe2x80x9coptionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyxe2x80x9d mean unsubstituted lower alkyl groups as above-named or the lower alkyl groups having substituent(s) at substitutable, optional position(s), said one, two or more, preferably one or two same or different substituents being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl.
Among the above lower alkylcarbamoyl as the substituent, for example, methylcarbamoyl and ethylcarbamoyl are preferred.
Among the di-lower alkylcarbamoyl as the substituent, for example, dimethylcarbamoyl and diethylcarbamoyl are preferred.
Preferred substituents include hydroxyl, amino and carbamoyl groups.
As the R1 lower alkyl, for example, methyl, ethyl and propyl are preferred.
Thus, specific examples of R1 include hydrogen, methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, carbamoylmethyl, 2-carbamoylethyl, methylcarbamoylmethyl, 2-methylcarbamoylethyl, dimethylcarbamoylmethyl, 2-dimethylcarbamoylethyl, 4-imidazolylmethyl and 2-(4-imidazolyl)ethyl. Of those, hydrogen, methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, carbamoylmethyl and 2-carbamoylethyl are preferred, in particular, hydrogen is preferred.
R2, R3, R4 and R5 each independently stands for hydrogen or optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl, or R2 and R3, or R4 and R5, may together stand for, independently of each other, optionally substituted trimethylene, propenylene, tetramethylene or 2-butenylene group, the substituent being selected from the group consisting of oxo, hydroxyl, amino, lower alkoxy, lower alkanoyloxy, lower alkylamino, di-lower alkylamino, (imino-lower alkyl)amino, lower alkanoylamino, lower alkoxycarbonylamino, (lower alkylcarbamoyl)amino, lower alkylsulfonylamino, guanidino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, imidazolyl and a group represented by xe2x80x94R7.
Said xe2x80x9coptionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyxe2x80x9d mean unsubstituted lower alkyl groups as above-named or the lower alkyl groups having substituent(s) at substitutable, optional position(s), said one, two ore more, preferably one or two same or different substituents being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl.
Among the lower alkylcarbamoyl as the substituent, for example, methylcarbamoyl and ethylcarbamoyl are preferred.
Among the di-lower alkylcarbamoyl as the substituent, for example, dimethylcarbamoyl and diethylcarbamoyl are preferred.
Preferred substituents include hydroxyl, amino, carbamoyl and imidazolyl groups.
As the lower alkyl groups as R2, R3, R4 or R5, for example, methyl, ethyl and propyl are preferred.
Thus, examples of the optionally substituted lower alkyl as R2, R3, R4 or R5 are same to those earlier named optionally substituted lower alkyl groups as R1, among which methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, carbamoylmethyl, 2-carbamoylethyl and 4-imidazolylmethyl, inter alia, methyl and 4-imidazolylmethyl, are preferred.
Said xe2x80x9coptionally substituted trimethylene, propenylene, tetramethylene or 2-butenylene group, the substituent being selected from the group consisting of oxo, hydroxyl, amino, lower alkoxy, lower alkanoyloxy, lower alkylamino, di-lower alkylamino, (imino-lower alkyl)amino, lower alkanoylamino, lower alkoxycarbonylamino, (lower alkylcarbamoyl)amino, lower alkylsulfonylamino, guanidino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, imidazolyl and a group represented by xe2x80x94R7xe2x80x9d mean unsubstituted trimethylene, propenylene, tetramethylene and 2-butenylene groups, or those having substituent(s) at substitutable, optional position(s), said one, two or more, preferably one or two same or different substituents being selected from the group consisting of oxo, hydroxyl, amino, lower alkoxy, lower alkanoyloxy, lower alkylamino, di-lower alkylamino, (imino-lower alkyl)amino, lower alkanoylamino, lower alkoxycarbonylamino, (lower alkylcarbamoyl)amino, lower alkylsulfonylamino, guanidino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, imidazolyl and a group represented by xe2x80x94R7.
Among the lower alkoxy as the substituent, for example, methoxy, ethoxy, propoxy and tert-butoxy are preferred.
Among the lower alkanoyloxy as the substituent, for example, acetoxy and propionyloxy are preferred.
Among the lower alkylamino as the substituent, for example, methylamino, ethylamino and propylamino are preferred.
Among the di-lower alkylamino as the substituent, for example, dimethylamino and diethylamino are preferred.
Among the (imino-lower alkylamino as the substituent, for example, formimidoylamino, acetimidoylamino and propanimidoylamino are preferred.
Among the lower alkanoylamino as the substituent, for example, acetylamino and propionylamino are preferred.
Among the lower alkoxycarbonylamino as the substituent, for example, methoxycarbonylamino, ethoxycarbonylamino and propoxycarbonylamino are preferred.
Among the (lower alkylcarbamoyl)amino as the substituent, for example, (methylcarbamoyl)amino, (ethylcarbamoyl)amino and (propylcarbamoyl)amino are preferred.
Among the lower alkylsulfonylamino as the substituent, for example, methylsulfonylamino, ethylsulfonylamino and propylsulfonylamino are preferred.
Among the lower alkoxycarbonyl as the substituent, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl are preferred.
Among the lower alkylcarbamoyl as the substituent, for example, methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl are preferred.
Among di-lower alkylcarbamoyl as the substituent, for example, dimethylcarbamoyl and diethylcarbamoyl are preferred.
R7 stands for optionally substituted lower alkyl group, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl lower alkoxycarbonyl and imidazolyl.
xe2x80x9cOptionally substituted lower alkyl group, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxycarbonyl and imidazolylxe2x80x9d means unsubstituted lower alkyl groups as above-named or the lower alkyl groups having substituent(s) at substitutable, optional position(s), said one, two or more, preferably one or two same or different substituents being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, lower alkoxycarbonyl and imidazolyl.
Among the lower alkylcarbamoyl as the substituent, for example, methylcarbamoyl, ethylcarbamoyl and propylcarbamoyl are preferred.
Among the di-lower alkylcarbamoyl as the substituent, for example, dimethylcarbamoyl and diethylcarbamoyl are preferred.
Among the lower alkoxycarbonyl as the substituent, for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl are preferred.
As the substituent groups, for example, hydroxyl, amino and carbamoyl are preferred.
As the lower alkyl groups as R7, for example, methyl and ethyl are preferred.
Hence, preferred examples of R7 include methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, carbamoylmethyl, 2-carbamoylethyl, methylcarbamoylmethyl, 2-methylcarbamoylethyl, dimethylcarbamoylmethyl, 2-dimethylcarbamoylethyl, methoxycarbonylmethyl, 2-methoxycarbonylethyl, 4-imidazolylmethyl and 2-(4-imidazolyl)ethyl. In particular, methyl, ethyl, hydroxymethyl, aminomethyl and carbamoylmethyl are preferred.
As the substituent(s) on trimethylene, propenylene, tetramethylene or 2-butenylene, oxo, hydroxyl, amino, lower alkoxy, lower alkylamino and di-lower alkylamino, inter alia, hydroxyl and amino, are preferred.
Among trimethylene, propenylene, tetramethylene and 2-butenylene groups, trimethylene is the preferred.
Accordingly, among those optionally substituted trimethylene, propenylene, tetramethylene and 2-butenylene formed together by R2 and R3, or R4 and R5, unsubstituted trimethylene and hydroxyl- or amino-substituted trimethylene are particularly preferred.
Preferred embodiments of R2, R3, R4 and R5 include one wherein R2, R3, R4 and R5 are hydrogen atoms at the same time; those wherein either one of R2 and R3 is hydrogen and the other is an optionally substituted lower alkyl, the substituent being selected from the group consisting of hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl, and both R4 and R5 are hydrogen atoms; and those wherein R2 and R3, or R4 and R5 together stand for, independently of each other, optionally substituted trimethylene, the substituent being selected from the group consisting of oxo, hydroxyl, amino, lower alkoxy, lower alkanoyloxy, lower alkylamino, di-lower alkylamino, (imino-lower alkylamino, lower alkanoylamino, lower alkoxycarbonylamino, (lower alkylcarbamoyl)amino, lower alkylsulfonylamino, guanidino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, imidazolyl and xe2x80x94R7 (here R7 has the earlier defined signification).
Among the compounds represented by the general formula [I], therefore, for example those in which Ar1, Ar2 and Ar3 are each independently phenyl which may be halogen- or lower alkyl-substituted, n is 1 or 2, s is 1, and R1 is hydrogen, are preferred. In particular, the compounds represented by the following general formula [I-a]: 
[wherein A1 stands for a group represented by the formula [a1] or [b1]
R2a and R3a each independently stands for hydrogen, or optionally substituted lower alkyl, the substituent being selected from hydroxyl, amino, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl and imidazolyl; R8 stands for hydrogen, halogen or lower alkyl; R60, R61, R71 and Qxe2x88x92 have the earlier defined significations];
the compounds represented by the general formula [I-b]: 
[wherein A1a stands for a group of the formula [a1]
and R8 and R60 have the earlier defined significations];
the compounds represented by the general formula [I-c]: 
[in which A1 and R8 have the earlier defined significations];
the compounds represented by the general formula [I-d]: 
[in which A1a and R8 have the earlier defined significations];
and the compounds represented by the general formula [I-e]
[in which n1 stands for 1 or 2; Re1, Re2, Re3 and Re4 each independently stands for hydrogen, hydroxyl, amino, lower alkoxy, lower alkanoyloxy, lower alkylamino, di-lower alkylamino, (imino-lower alkyl)amino, lower alkanoylamino, lower alkoxycarbonylamino, (lower alkylcarbamoyl)amino, lower alkylsulfonylamino, guanidino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl, imidazolyl and a group represented by xe2x80x94R7; or Re1 and Re2 together signify oxo group; and A1, R7 and R8 have the earlier defined significations]
are preferred.
Among the compounds represented by the general formula [I-a], the preferred are those in which R2a is hydrogen and R3a is hydrogen, methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, aminomethyl, 2-aminoethyl, carbamoylmethyl, 2-carbamoylethyl or 4-imidazolylmethyl, in particular, hydrogen or 4-imidazolylmethyl; or those in which R2a, is methyl and R3a is hydrogen.
Among the compounds represented by the general formula [I-e], the preferred are those in which Re1, Re2, Re3 and Re4 each independently is hydrogen, hydroxyl, amino, methoxy, ethoxy, propoxy, tert-butoxy, acetoxy, methylamino, ethylamino, propylamino, dimethylamino and diethylamino, or those in which Re1 and Re2 together form oxo group and Re3 and Re4 both are hydrogen atoms. In particular, the compounds in which Re1 is hydroxyl or amino, preferably hydroxyl, and Re2, Re3 and Re4 are hydrogen atoms at the same time; those in which both Re1 and Re3 are hydroxyl groups and both Re2 and Re4 are hydrogen atoms; or those in which both Re1 and Re2 are hydroxyl groups and both Re3 and Re4 are hydrogen atoms are advantageous. Inter alia, the compounds where A1 is a group represented by the formula [b1], R61 and R71 are at the same time methyl, ethyl, propyl, 2-propenyl or cyclopropylmethyl, in particular, ethyl, propyl or cyclopropylmethyl; or R61 is cyclohexylmethyl and R71 is methyl; or R61 and R71 together form tetramethylene, 2-butenylene or pentamethylene, in particular, tetramethylene or 2-butenylene, can be advantageously used.
Referring to those general formulae [I-a], [I-b], [I-c], [I-d] and [I-e], convenient R8 is, for example, hydrogen or halogen, in particular, hydrogen or fluorine.
Now processes for preparing the compounds of the present invention are explained.
The compounds of the present invention can be prepared by the following processes or those as shown in working examples, it being understood that the preparation processes of compounds of this invention are not limited to those reaction examples.
Production Process 1
Carboxylic acid of the general formula [II]: 
[in which Ar1p, Ar2p and Ar3p each independently stands for optionally substituted phenyl, the substituent being selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkoxy and di-lower alkylcarbamoyl and optionally protected hydroxyl, carbamoyl and lower alkylcarbamoyl; and R1p stands for hydrogen or optionally substituted lower alkyl, the substituent being selected from the group consisting of di-lower alkylcarbamoyl, optionally protected hydroxyl, amino, carbamoyl, lower alkylcarbamoyl and imidazolyl groups]
or salt or reactive derivative thereof is reacted with a compound of the general formula [III]: 
[in which Aap stands for a group of the formula [a0p]
R2p, R3p, R4p and R5p each independently stands for hydrogen or optionally substituted lower alkyl, the substituent being selected from the group consisting of di-lower alkylcarbamoyl and optionally protected hydroxyl, amino, carbamoyl, lower alkylcarbamoyl and imidazolyl groups, or R2p and R3p, or R4p and R5p, together form, each independently of the other pair, optionally substituted trimethylene, propenylene, tetramethylene or 2-butenylene, the substituent being selected from the group consisting of lower alkoxy, lower alkanoyloxy, di-lower alkylamino, lower alkoxycarbonyl, di-lower alkylcarbamoyl, a group represented by xe2x80x94R7p and optionally protected oxo, hydroxyl, amino, lower alkylamino, (imino-lower alkyl)amino, lower alkanoylamino, lower alkoxycarbonylamino, (lower alkylcarbamoyl)amino, lower alkylsulfonylamino, guanidino, carbamoyl, lower alkylcarbamoyl and imidazolyl groups; R7p stands for optionally substituted lower alkyl, the substituent being selected from the group consisting of di-lower alkylcarbamoyl and lower alkoxycarbonyl, and optionally protected hydroxyl, amino, carbamoyl, lower alkylcarbamoyl and imidazolyl groups; R60p stands for imino-protecting group, C1-C10 alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring potion being optionally substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl; and k, m, n, s, X and Y have the earlier defined significations]
or salt thereof, to form a compound represented by the general formula [IV-1]
[in which Aap, Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, X and Y have the earlier defined significations]
or a salt thereof, and if necessary the protective group(s) are removed to produce a compound represented by the general formula [I-1]
[in which A1 stands for a group of the formula [a0]
Ar1, Ar2, Ar3, k, m, n, R2, R3, R4, R5, R60, s, X and Y have the earlier defined significations]
or salts thereof.
The above production process 1 is the process for producing, among the compounds of the present invention which are represented by the general formula [I], those in which A in said general formula is a group represented by the formula [a0]
[in which R60 and s have the earlier defined significations], i.e., the compounds expressed by the earlier given general formula [I-1].
Where the reactants in the above reaction contain oxo, hydroxyl, amino or imino groups which do not participate in the reaction, those groups are preferably suitably protected by respective protective groups before the reaction, and are deprotected after the reaction.
Examples of xe2x80x9coxo-protective groupxe2x80x9d include acetals and ketals such as ethylene ketal, trimethylene ketal and dimethyl ketal.
Examples of xe2x80x9chydroxyl-protective groupxe2x80x9d include alkyl such as tert-butyl; substituted silyls such as trimethylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl; lower alkoxymethyl such as methoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl such as benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl and triphenylmethyl; and acyl such as formyl and acetyl. In particular, tert-butyl, benzyl, methoxymethyl, tetrahydropyranyl, triphenylmethyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl and acetyl groups are preferred.
Examples of xe2x80x9camino- or imino-protective groupxe2x80x9d include aralkyl such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and triphenylmethyl; lower alkanoyl such as formyl, acetyl, propionyl, butyryl and pivaloyl; benzoyl; arylalkanoyl such as phenylacetyl and phenoxyacetyl; lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl and tert-butoxycarbonyl; aralkyloxycarbonyl such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and phenethyloxycarbonyl; lower alkylsilyl such as trimethylsilyl and tert-butyldimethylsilyl; phthaloyl; and aralkylidene such as benzylidene, p-chlorobenzylidene and o-nitrobenzylidene. In particular, acetyl, pivaloyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl and tert-butoxycarbonyl groups are preferred.
The reaction of a carboxylic acid of the general formula [II] or salt or reactive derivative thereof with a compound expressed by the general formula [III] or salt thereof is usually carried out using 1-5 mols, preferably 1-2 mols, of the carboxylic acid of the formula [II] or salt or reactive derivative thereof, per mol of the compound of the formula [III] or salt thereof.
xe2x80x9cSaltxe2x80x9d of said carboxylic acid of the formula [II] means base addition salt at the carboxyl group, examples of which include alkali metal salt such as sodium salt and potassium salt; alkaline earth metal salt such as calcium salt and magnesium salt; ammonium salt; and organic amine salt such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, procaine salt and N,Nxe2x80x2-dibenzylethylenediamine salt.
Examples of xe2x80x9creactive derivativexe2x80x9d of the carboxylic acid of the formula [II] are mixed acid anhydrides, active esters and active amides.
Where said carboxylic acid of the formula [II] or salt thereof is used in the reaction, the reaction is preferably carried out in the presence of a condensing agent such as, for example, N,Nxe2x80x2-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, diphenylphosphoryl azide and dipyridyldisulfide-triphenylphosphin, in particular, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
The use rate of the condensing agent is not strictly limited, while it is usually in the range of 1-5 mols, preferably 1-2 mols, per mol of the carboxylic acid of the formula [II] or salt thereof
The reaction is usually carried out in an inert solvent, examples of which include diethyl ether, tetrahydrofuran, N,N-dimethylformamide, dioxane, benzene, toluene, chlorobenzene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane and trichloroethylene; and mixtures of those solvents. In particular, diethyl ether, tetrahydrofuran, N,N-dimethylformamide, chloroform and dioxane are preferred.
The reaction temperature usually ranges from xe2x88x9270xc2x0 C. to the boiling point of the solvent used in the reaction, preferably xe2x88x9220xc2x0 C.-100xc2x0 C.
The reaction time usually ranges from 5 minutes to 7 days, preferably from 10 minutes to 24 hours.
The reaction may also be carried out in the presence of a base, for smooth progress of the reaction.
Examples of useful base include aliphatic tertiary amine such as triethylamine and diisopropylethylamine; and aromatic amines such as pyridine, 4-dimethylaminopyridine and quinoline. Of those, triethylamine and 4-dimethylaminopyridine are preferred.
The use rate of said base can be within a range of 1-5 mols, preferably 1-2 mols, per mol of the carboxylic acid expressed by the formula [II] or salt or reactive derivative thereof.
Mixed acid anhydride of carboxylic acid of the formula [II] can be obtained by reacting carboxylic acid of the formula [II] with, for example, alkyl chlorocarbonate such as ethyl chlorocarbonate; aliphatic carboxylic acid chloride such as acetyl chloride, pivaloyl chloride and the like, according to usual method.
Active esters of carboxylic acid of the formula [II] can be obtained by reacting the carboxylic acid of said formula [II] with, for example, an N-hydroxy compound such as N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole; or a phenol compound such as 4-nitrophenol, 2,4-dinitrophenol, 2,4,5-trichlorophenol, pentachlorophenol or the like; in the presence of a condensing agent, e.g., N,Nxe2x80x2-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, diphenylphosphoryl azide or dipyridyl disulfide-triphenylphosphine, according to usual method.
Active amide of the carboxylic acid of the formula [II] can be obtained by reacting the carboxylic acid of formula [II] with 1,1xe2x80x2-carbonyldiimidazole, 1,1xe2x80x2-carbonylbis(2-methylimidazole) or the like according to usual methods.
After completion of the reaction, ordinary treatment is given to provide crude product of a compound expressed by the general formula [IV-1], which is optionally purified according to usual method and further if necessary subjected to a reaction for removing protective group(s) of oxo, hydroxyl, amino or imino, to provide a compound of the formula [I-1].
Method for removing the protective group(s) differs depending on the kind of the protective group and stability of the object compound [I-1], but those methods known per se may be employed, for example, those taught in Protective Groups in Organic Synthesis, T. W. Greene, John Wiley and Sons Co. (1981) or methods analogous thereto, for example, solvolysis using an acid or base, that is, using for example 0.01 molxe2x80x94a large excess of an acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid or the like, or an equimolar or largely excessive amount of a base, preferably potassium hydroxide, calcium hydroxide or the like; chemical reduction using hydrogenated metal complex or catalytic reduction using palladium-carbon catalyst or Raney nickel catalyst.
Production Process 2
By following the steps of reacting a compound expressed by the following general formula [IV-1a]: 
[in which Aaa signifies a group represented by the formula [a0a]
Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, s, X, and Y have the earlier defined significations]
or a salt thereof, with a compound of a general formula [V]
Oxe2x95x90R61axe2x80x83xe2x80x83[V]
[in which R61a signifies C1-C10 alkylidene, lower alkenylidene, cycloalkylidene, cycloalkyl lower alkylidene whose ring portion may be substituted with lower alkyl, cycloalkenyl lower alkylidene or aralkylidene]
under reducing conditions to form a compound of a general formula [IV-1b]: 
[in which Aab signifies a group represented by the formula [a0b]
R61b signifies C1-C10 alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl; Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, s, X, and Y have the earlier defined significations]
or a salt thereof, and if necessary removing the protective groups, a compound of the general formula [I-2]: 
[in which Aab, Ar1, Ar2, Ar3, k, m, n, R1, R2, R3, R4, R5, s, X and Y have the earlier defined significations]
or a salt thereof can be produced.
The production process 2 is a process for producing, among the compounds of the present invention represented by the general formula [I], those in which A is the group expressed by the formula [a0b]: 
[in which R61b and s have the earlier defined significations], i.e., the compounds expressed by the general formula [I-2].
Said xe2x80x9cC1-C10 alkylidene, lower alkenylidene, cycloalkylidene, cycloalkyl-lower alkylidene whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkylidene or aralkylidenexe2x80x9d as R61a mean those which are capable of becoming the corresponding xe2x80x9cC1-C10 alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkylxe2x80x9d, respectively, after completion of the above reaction.
The reaction of a compound represented by the general formula [IV-1a] or a salt thereof with a compound represented by the general formula [V] under reducing conditions is a so-called reductive alkylation reaction of an amino group, and conducted using a mol or molar excess, preferably 1-2 mols, of the compound of the general formula [V] per mol of the compound of the general formula [IV-1a] or salt thereof, in the presence of a reducing agent or under catalytic reduction, in an inert solvent which has no adverse effect on the reaction.
As the inert solvent, for example, alcohols such a methanol or ethanol; ethers such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons such as benzene or toluene; halogenated hydrocarbons such as dichloroethane; or their mixtures can be named, in particular, methanol, ethanol, tetrahydrofuran, dichloroethane or toluene being preferred.
Where the reaction is carried out in the presence of a reducing agent, examples of useful reducing agent include complex metal hydrides such as sodium boron hydride, sodium cyanoboron hydride, aluminium lithium hydride, aluminium diisobutyl hydride and sodium triacetoxyboron hydride; in particular, sodium boron hydride, sodium cyanoboron hydride or sodium triacetoxyboron hydride being preferred.
The use rate of said reducing agent is usually a mol to molar excess, preferably 1-10 mols, per mol of the compound represented by the general formula [IV-1a] or salt thereof.
The reaction temperature usually ranges from about xe2x88x9230xc2x0 C. to about 200xc2x0 C., preferably from about 0xc2x0 C. to 100xc2x0 C.; and the reaction time usually ranges from an instant to 7 days, preferably from an instant to 24 hours.
Where the reaction is carried out under catalytic reduction, for example, palladium-carbon catalyst, Raney nickel catalyst or the like is used as the catalyst.
The hydrogen pressure in the catalytic reduction reaction is usually and conveniently from atmospheric to 2 atmospheres, and the use rate of the catalyst is usually from {fraction (1/100)} to 1, preferably {fraction (1/100)}-{fraction (1/10)} by weight to the starting compound [IV-1a].
The reaction temperature usually ranges from about xe2x88x9230xc2x0 C. to 50xc2x0 C., preferably from about 0xc2x0 C. to room temperature, and the reaction time usually ranges from an instant to 7 days, preferably from an instant to 24 hours.
As the means of reduction in this reaction, the above-described reduction method using the complex metal hydride is convenient.
This reaction may be conducted under weakly acidic conditions, in which Schiff base is easily formed. As examples of acid useful for pH control for that purpose include p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, acetic acid and trifluoroacetic acid.
In this step it is also possible not to conduct the reaction in the presence of a reducing agent or under catalytic reduction, but to first react a compound of the general formula [IV-1a] or salt thereof with a compound of the general formula [V] to form an imine in advance, and then to subject said imine to a reducing reaction.
In the above reaction where such groups as oxo, hydroxyl, amino or imino which do not participate in the reaction are present in the reactants, it is desirable to suitably protect them with protective groups of oxo, hydroxyl, amino or imino, respectively, before the reaction and to remove the protective groups after the reaction.
As the protective groups suitable for oxo, hydroxyl, amino or imino, those respective protective groups as described in relation to the production process 1 are applicable as they are.
Upon completion of the reaction, after removing the protective groups in the compound of the general formula [IV-1b] where they are present; or where no protective group is present in the product, without such an intervening treatment, the product is processed in the usual manner to produce a compound of the general formula [I-2].
For removing the protective groups and conducting the post-treatment, those methods as described as to the production process 1 are applicable.
Production Process 3
By following the steps of reacting a compound of the general formula [IV-1a]: 
[in which Aaa, Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, X and Y have the earlier defined significations]
or a salt thereof with a compound of the general formula [VI-1]
L1xe2x80x94R61bxe2x80x83xe2x80x83[VI-1]
[in which L1 signifies a leaving group, and R61b has the earlier defined signification]
to form a compound expressed by the general formula [IV-1b]
[in which Aab, Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, X and Y have the earlier defined significations]
or salt thereof, and if necessary removing the protective groups, a compound of the general formula [I-2]
[in which Aab, Ar1, Ar1, Ar2, Ar3, k, m, n, R1, R2, R3, R4, R5, s, X and Y have the earlier defined significations]
or salt thereof can be produced.
The production process 3 is a method for producing the compounds expressed by the general formula [I-2], same as above production process 2.
Examples of xe2x80x9cleaving groupxe2x80x9d expressed by L1 include halogen atoms such as chlorine, bromine and iodine; alkylsulfonyloxy groups such as methylsulfonyloxy; or arylsulfonyloxy groups such as p-toluenesulfonyloxy.
The reaction of a compound of the general formula [IV-1a] or a salt thereof with a compound of the general formula [IV-1] is usually conducted using a mol or molar excess, preferably 1-2 mols, of the compound of the formula [VI-1] per mol of the compound of formula [IV-1a] or salt thereof, in an inert solvent which is not detrimental to the reaction.
As such inert solvent, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene; and aprotic polar solvents such as dimethylsulfoxide, N,N-dimethylformamide, acetonitrile and hexamethylphosphoric triamide; or mixtures of the foregoing can be used.
For smooth progress, the reaction may be carried out in the presence of base and/or a reaction assistant.
As the base, for example, alkali metal bicarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary aliphatic amines such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline can be used. Of those, potassium carbonate, N,N-diisopropylethylamine and triethylamine are preferred.
The use rate of the base is usually a mol or molar excess, preferably 1-3 mols, per mol of the compound of the formula [IV-1a].
As assistant useful for the reaction, for example, alkali metal iodides such as lithium iodide, sodium iodide and potassium iodide may be named. Of these, potassium iodide is preferred.
The use rate of the assistant is usually from catalytic to excessive amount, preferably from catalytic amount to one equivalent, to the compound of the formula [IV-1a].
The reaction temperature may usually range from about 0xc2x0 C. to the boiling point of the solvent used in the reaction, and the reaction time may usually range from 10 minutes to 48 hours.
In the above reaction where such groups as oxo, hydroxyl, amino or imino which do not participate in the reaction are present in the reactants, it is desirable to suitably protect them with protective groups of oxo, hydroxyl, amino or imino, respectively, before the reaction and to remove the protective groups after the reaction.
As the protective groups suitable for oxo, hydroxyl, amino or imino, those respective protective groups as described in relation to the production process 1 are applicable as they are.
Upon completion of the reaction, after removing the protective groups in the compound of the general formula [IV-1b] where they are present; or where no protective group is present in the product, without such an intervening treatment, the product is processed in the usual manner to produce a compound of the general formula [I-2].
For removing the protective groups and conducting the post-treatment, those methods as described as to the production process 1 are applicable.
Production Process 4
By following the steps of reacting a compound of the general formula [VI-2]:
R71axe2x80x94L2xe2x80x83xe2x80x83[VI-2]
[in which L2 signifies a leaving group; R71a signifies C1-C10 alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl whose ring portion may be substituted with lower alkyl, cycloalkenyl-lower alkyl or aralkyl]
or a salt thereof with a compound of the general formula [IV-1b]: 
[in which Aab, Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, s, X and Y have the earlier defined significations]
or a salt thereof, to form a compound expressed by the general formula [IV-2]: 
[in which Z signifies anion; Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, R61b, R71a, s, X and Y have the earlier defined significations]
and if necessary removing the protective group(s) and/or exchanging the anion, a compound of the general formula [I-3]: 
[in which Aba signifies a group expressed by the formula [b0a]
Ar1, Ar2, Ar3, k, m, n, R1, R2, R3, R4, R5, R61b, R71a, s, X, Y and Qxe2x88x92 have the earlier defined significations]
can be produced.
The production process 4 is a method for producing, among the compounds of the present invention represented by the general formula [I], those in which A is a group expressed by the formula [b0a]: 
[in which R61b, R71a, s and Qxe2x88x92 have the earlier defined significations],
i.e., the compounds represented by the general formula [I-3].
As the xe2x80x9cleaving groupxe2x80x9d expressed by L2, those leaving groups exemplified as L1 in the production process 3 are equally applicable.
In the above reaction where such groups as oxo, hydroxyl, amino or imino which do not participate in the reaction are present in the reactants, it is desirable to suitably protect them with protective groups of oxo, hydroxyl, amino or imino, respectively, before the reaction and to remove the protective groups after the reaction.
As the protective groups suitable for oxo, hydroxyl, amino or imino, those respective protective groups as described in relation to the production process 1 are applicable as they are.
The reaction of a compound expressed by the general formula [VI-2] or salt thereof with a compound of the general formula [IV-1b] or salt thereof is usually carried out using a mol or molar excess, preferably a large molar excess, of the compound of formula [VI-2] or salt thereof, per mol of the compound of the formula [IV-1b] or salt thereof, in the absence of a solvent or in an inert solvent which is not detrimental to the reaction, non-use of solvent being preferred.
As such inert solvent, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; and aprotic polar solvents such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile and hexamethylphosphoric triamide; or mixtures of the foregoing can be used, in particular, chloroform and acetonitrile being preferred.
For smooth progress, the reaction may be carried out in the presence of base and/or a reaction assistant.
As the base, for example, alkali metal bicarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary aliphatic amines such as trimethylamine, diethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline can be used. Of those, potassium carbonate, diethylamine, triethylamine and N,N-diisopropylethylamine are particularly suitable.
The use rate of the base is usually a mol or molar excess, preferably 1-3 mols, per mol of the compound of the formula [IV-1b].
As assistant useful for the reaction, for example, alkali metal iodides such as lithium iodide, sodium iodide and potassium iodide may be named. Of these, potassium iodide is preferred.
The use rate of the assistant is usually from catalytic to excessive amount, preferably from catalytic amount to one equivalent, to the compound of the formula [IV-1b].
The reaction temperature may usually range from about 0xc2x0 C. to the boiling point of the solvent or reagent used in the reaction, preferably from 20xc2x0 C. to the boiling point of the solvent or reagent used in the reaction, and the reaction time may usually range from 10 minutes to 48 hours, preferably 1-10 hours.
Upon completion of the reaction, after removing the protective groups in the compound of the general formula [IV-2] where they are present; or where no protective group is present in the product, without such an intervening treatment, the product is processed in the usual manner to produce a compound of the general formula [I-3].
For removing the protective groups and conducting the post-treatment, those methods as described as to the production process 1 are applicable.
Those compounds of the general formula [I-3] are isolated as those having a certain or more than one kind of anions, and thereafter the anions can be changed to other desired anions.
As the method of changing anions, for example, one comprising adsorbing the formula [I-3] compound onto a column filled with an adequate carrier, treating the same with a salt of an acid having an excess of desired anions, and eluting the intended formula [I-3] compound as formed.
Production Process 5
By following the steps of reacting a compound of the general formula [VII]:
L3xe2x80x94R71bpxe2x80x94L4xe2x80x83xe2x80x83[VII]
[in which L3 and L4 each independently signifies a leaving group, and R71bp signifies optionally substituted trimethylene, tetramethylene, 2-butenylene, pentamethylene, 3-oxapentamethylene or 2,3-epoxytetramethylene, the substituent being selected from the group consisting of lower alkyl, lower alkoxy, and optionally protected oxo and hydroxyl]
or a salt thereof with a compound of a general formula [IV-1a]
[in which Aaa, Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, s, X and Y have the earlier defined significations]
or a salt thereof, to form a compound of the general formula [IV-3]
[in which Ar1p, Ar2p, Ar3p, k, m, n, R1p, R2p, R3p, R4p, R5p, R71bp, s, X, Y and Zxe2x88x92 ave the earlier defined significations],
and if necessary removing protective groups and/or exchanging the anion, a compound expressed by the general formula [I-4]: 
[in which Abb signifies a group expressed by the formula [b0b]: 
Ar1, Ar2, Ar3, R1, R2, R3, R4, R5, R71b, k, m, s, X, Y and Qxe2x88x92 have the earlier defined significations]can be produced.
The production process 5 is a method for producing, among the compounds of the present invention represented by the general formula [I], those in which A is a group expressed by the formula [b0b]: 
[in which R71b, s and Qxe2x88x92 have the earlier defined significations],
i.e., the compounds represented by the general formula [I-4].
As the xe2x80x9cleaving groupxe2x80x9d expressed by L3 or L4, those exemplified as L1 in the production process 3 are applicable independently of each other.
In the above reaction where such groups as oxo, hydroxyl, amino or imino which do not participate in the reaction are present in the reactants, it is desirable to suitably protect them with protective groups of oxo, hydroxyl, amino or imino, respectively, before the reaction and to remove the protective groups after the reaction.
As the protective groups suitable for oxo, hydroxyl, amino or imino, those respective protective groups as described in relation to the production process 1 are applicable as they are.
The reaction of a compound expressed by the general formula [IV-1a] or salt thereof with a compound of the general formula [VII] or salt thereof is usually carried out using a mol or molar excess, preferably 1-5 mols, of the compound of the formula [VII] or salt thereof, per mol of the compound of the formula [IV-1a] or salt thereof, in an inert solvent which is not detrimental to the reaction.
As such inert solvent, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene, toluene, chlorobenzene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; and aprotic polar solvents such as dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile and hexamethylphosphoric triamide; or mixtures of the foregoing can be used, among which chloroform and acetonitrile are preferred.
For smooth progress, the reaction may be carried out in the presence of base and/or a reaction assistant.
As the base, for example, alkali metal bicarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; tertiary aliphatic amines such as trimethylamine, diethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (IBN); and aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline can be used. Of those, potassium carbonate, diethylamine, triethylamine and N,N-diisopropylethylamine are preferred.
The use rate of the base is usually a mol or molar excess, preferably 1-3 mols, per mol of the compound of the formula [IV-1a].
As assistant useful for the reaction, for example, alkali metal iodides such as lithium iodide, sodium iodide and potassium iodide may be named. Of these, potassium iodide is preferred.
The use rate of the assistant is usually from catalytic to excessive amount, preferably from catalytic amount to one equivalent, to the compound of the formula [IV-1a].
The reaction temperature may usually range from about 0xc2x0 C. to the boiling point of the solvent or reagent which is used in the reaction, preferably from 20xc2x0 C. to the solvent or reagent used in the reaction, and the reaction time may usually range from 10 minutes to 48 hours, preferably 1-10 hours.
Upon completion of the reaction, after removing the protective groups in the compound of the general formula [IV-3] where they are present; or where no protective group is present in the product, without such an intervening treatment, the product is processed in the usual manner or if necessary exchanged of the anions therein to produce a compound of the general formula [I-4].
For removing the protective groups and other post-treatments, those methods as described in the explanation of the production process 1 are applicable as they are, and for changing anions, the method as described as to above production process 4 is applicable as it is.
Isolation and purification of those compounds of the general formulae [I-1-], [I-2], [I-3] or [I-4] which are obtained in above processes can be accomplished by customarily practiced separation means such as column chromatography using silica gel, adsorptive resins and the like, thin-layer chromatography, liquid chromatography, solvent extraction or recrystallization-reprecipitation, applied singly or in combination.
Compounds of the general formula [I-1] or [I-2] are convertible to pharmaceutically acceptable salts by customary means and conversely, conversion from the salts to free compounds can also be conducted following customary means.
As those compounds represented by general formulae [II], [III], [IV-1a], [V], [VI-1], [VI-2] or [VII], commercial products may be used, or they can be prepared by methods which are described in literature references (cf. M. Bodansky and M. A. Ondetti, Peptide Synthesis, Interscience, New York, 1966; F. M. Finn and K. Hoffman, The Proteins, Vol. 2, ed. by H. Nenrath and R. L. Hill, Academic Press Inc., New York, 1976; Nobuo Izumiya, et al., Peptide Gosei (synthesis), Maruzen Co., 1975; and Official Patent KOKAI (aid-open) Gazette, KOKAI No. Sho 62(1987)-215588), methods analogous to the above, methods described in the following or those used in working and referential examples given in this specification.
Production Method A 
[in the above formulae, P1 and P3 signify protective groups of amino or imino group; P2 signifies a protective group of imino group; Xa signifies carbonyl group; Ya signifies nitrogen atom; and k, m, n, R2p, R3p, R4p, R5p, R61a, R61b and s have the earlier defined significations].
This production method is that for producing the compounds represented by the general formula [III-1], according to which the compounds of the general formula [III-1] can be produced by the steps of having a compound of the general formula 2 act on a compound of the general formula 1 to form a compound of the general formula 3; removing therefrom the protective group P2 to form a compound 4 on which a compound of the general formula [V] is acted to form a compound of the general formula 5; removing therefrom the protective group P1 to form a compound 6 on which a compound of the general formula 7 is acted to form a compound of the general formula 8; and finally removing therefrom the protective group P3.
The step of preparing a compound 3 from a compound 1 and that of preparing a compound 3 from a compound 1 can each be conducted similarly to the step in the production process 1 of reacting a carboxylic acid of the general formula [II] or salt or reactive derivative thereof with a compound of the general formula [III] or salt thereof, and hence the reaction conditions earlier described about the reaction can be applied.
As examples of the protective groups P1, P2 or P3 for amino or imino group, those used as to the production process 1 can be named.
Steps for removing said protective groups can each be conducted following those methods taught in the literature references cited in respect of said production process 1.
The step of producing a compound 5 from a compound 4 can be conducted in the manner similar to the step of reacting a compound of the general formula [IV-1a] or salt thereof with a compound of the general formula [V] in the production process 2, and hence similar conditions are applicable as the reaction conditions.
Furthermore, as those compounds expressed by the general formulae 1, 2 or 7, either those chemicals on the market may be used or they may be prepared according to known processes, those described in the working or referential examples given in this specification or those analogous thereto, if necessary in suitable combinations.
Production Method B 
[in which k, m, n, P1, P2, P3, R2p, R3p, R4p, R5p, s, Xa and Ya have the earlier defined significations].
This production method is that for preparing the compounds represented by the general formula [III-2]. According to this method, the compounds of the general formula [III-2] can be produced by the steps of converting a compound of the general formula 3 to one of the general formula 9 by removing the protective group P1 from the former; having a compound of the general formula 7 act on said compound 9 to form a compound of the general formula 10; and finally removing the protective group P3 from said compound 10.
The step of preparing a compound 10 from a compound 9 can be conducted similarly to the step in the production process 1 of reacting a carboxylic acid of the general formula [II] or salt or reactive derivative thereof with a compound of the general formula [III] or salt thereof, and hence the reaction conditions earlier described about the reaction can be applied.
Steps for removing the protective groups of amino or imino, which are expressed as P1 or P3,can each be conducted following those methods taught in the literature references cited in respect of said production process 1.
Production Method C 
[in which Ra stands for lower alkyl; and Ar1p, Ar2p, Ar3p, k, m, n, P1, P2, R1p, R2p, R3p, R4p, R5p, s, Xa and Ya have the earlier defined significations].
This production method is that for producing the compounds represented by the general formula [IV-1aa], according to which the compounds of the general formula [IV-1aa] can be produced by the steps of having a compound of the general formula 12 act on a compound of the general formula 11 to form a compound of the general formula 13; removing therefrom the protective group P1 to form a compound 14 on which a compound of the general formula [II] is acted to form a compound of the general formula 15; removing therefrom the lower alkyl Ra to form a compound 16 on which a compound of the general formula 2 is acted to form a compound of the general formula [IV-1c]; and finally removing therefrom the protective group P2.
The step of preparing a compound 13 from a compound 11, that of preparing a compound 15 from a compound 14 and that of preparing a compound [IV-1c] from a compound 16 can each be conducted similarly to the step in the production process 1 of reacting a carboxylic acid of the general formula [II] or salt or reactive derivative thereof with a compound of the general formula [III] or salt thereof, and hence the reaction conditions earlier described about the reaction can be applied.
Steps for removing said protective groups of amino or imino, which are expressed as P1 or P2, and for removing the lower alkyl expressed as Ra can each be conducted following those methods taught in the literature references cited in respect of said production process 1.
Furthermore, as those compounds expressed by the general formulae 11 or 12, either those chemicals on the market may be used or they may be prepared according to known processes, those described in the working or referential examples given in this specification or those analogous thereto, if necessary in suitable combinations.
Utility of those compounds of the present invention is demonstrated by the following results of the tests on inhibition of binding to muscarinic receptors and those on antagonism against various muscarinic receptors.
Tests on Inhibition of Binding to Muscarinic Receptors
These tests were performed according to a modification of the method of Hargreaves, et al. (Br. J. Pharmacol. 107: 494-501, 1992). Namely, muscarinic acetylcholine receptors of human m1, m2, m3, m4 and m5 expressed in CHO cells (Receptor Biology, Inc.) were incubated with 0.2 nM [3H]-N-methylscopolamine (82 Ci/mmol, New England Nuclear, Inc.) and a test compound to be tested in 0.5 ml of 50 mM Tris-HCl, 10 mM MgCl2, 1 mM EDTA solution (pH 7.4) for 120 minutes at room temperature (about 20-25xc2x0 C.), followed by suction filtration over a glass filter (UniFilter plate-GF/C; Packard). Then the filter was washed four times with 1 ml of ice-cold Tris-HCl buffer and dried at 50xc2x0 C. for an hour. After adding a scintillator (Microscinti 0; Packard), the radioactivity of [3H]-N-methylscopolamine binding to the filter was counted with a microplate scintillation counter (TopCount(trademark); Packard). Non-specific receptor binding of [3H]-N-methylscopolamine was measured by adding 1 xcexcM N-methylscopolamine. According to the method of Cheng and Prusoff (Biochem. Pharmacol. 22: 3099-3108, 1973), the binding affinity of a compound of the present invention for muscarinic receptors is expressed by dissociation constant (Ki) which is calculated from the concentration (IC50) of the test compound which achieves 50% inhibition of binding of [3H]-N-methylscopolamine, the labeled ligand. The results are shown in Tables 1-1 and 1-2.
As is clear from the results indicated in above Tables 1-1 and 1-2, those compounds of the present invention exhibited far higher binding-inhibitory activity to m3 receptor, than to m1, m2, m4 and m5 receptors.
Tests for Antagonism to Muscarinic Receptors (In Vitro)
1) Test for Antagonism to M2 Receptor in Isolated Rat Right Atrium
The test was performed according to a conventional method. Male SD strain rats (weighing 300-500 g) were killed by exsanguination, and from each of them the right atrium was isolated. Each preparation was isometrically suspended in a Magnus tube filled with 20 ml of Krebs-Henseleit solution (gassed with 95% O2-5% CO2 and kept at 32xc2x0 C.) with an initial tension of 0.5 g. The heart rate was recorded with a heart rate counter. After the preparation was equilibrated for 30 minutes, carbachol (10xe2x88x929 to 10xe2x88x926 M) was cumulatively administered from a low concentration to three-fold increasing doses and accompanying decrease in heart rate was measured to obtain a dose-responsecurve for the control experiment.
After the preparation was washed with fresh solution to restore the heart rate, a test compound was administered thereto. Ten minutes later, carbachol was cumulatively administered again. Responses to carbachol were expressed as percentages based on the heart rate before administration of carbachol as 100%. The antagonistic potency (KB value) of the test compound was determined from the degree of shift of the dose-response curve attributable to the treatment with individual test compound of the present invention.
The results were as shown in Tables 2-1 and 2-2.
2) Test for Antagonism to the Airway M3 Receptor in Isolated Rat Trachea
The test was performed according to a conventional method. Male SD strain rats (weighing 300-500 g) were killed by exsanguination, and from each of them the trachea was isolated. Annular segments (2 mm wide) were cut out from the trachea and cut transversely at the anterior cartilage part to make open ring preparation. Each preparation was suspended in a Magnus tube filled with 5 ml of Krebs-Henseleit solution (gassed with 95% O2-5% CO2 and kept at 32xc2x0 C.) with an initial tension of 1.0 g and a resting tension of 0.6 g. The tension of the preparation was recorded isometrically. After being equilibrated for an hour, the preparation was made to contract twice by treatment with 10xe2x88x924 M carbachol, and the second contraction induced by carbachol was used as the reference contraction. After washing the preparation with fresh solution to restore it to the base line, a test compound was administered thereto (or no treatment was given). Ten minutes later, carbachol (10.8 to 10xe2x88x923 M) was cumulatively administered in three-fold increasing doses to obtain a dose-response curve. The dose-responsecurve was plotted by expressing responses as percentages based on the reference contraction of the preparation as 100%. The antagonistic potency (KB value) of the test compound was determined from the degree of shift of the dose-responsecurve attributable to the treatment with the test compound. The results were as shown in Tables 2-1 and 2-2.
As is clear from the results indicated in above Tables 2-1 and 2-2, the compounds of the present invention exhibited far more powerful antagonism to the trachea M3 receptor than to the right atrium M2 receptor. Therefore, the compounds of the present invention are more selective for trachea M3 receptor.
Tests for Antagonism Against Muscarinic Receptors (In Vivo)
1) Test for Antagonism to M1 Receptor (Inhibitory Effects on McNeil-A-343-induced Vasopressor Reaction in Cervical Vertebrae-separated Rats)
Male SD strain rats (weighing 300-500 g) were anesthetized with intraperitoneal administration of pentobarbital (50 mg/kg). Each rat""s airway was cannulated by laryngotomy. Also by femoral incision, femoral artery and vein were isolated each and cannulated, which were used as routes for heart rate counting and chemical administration, respectively. Using a pulmotor for small animals (Type 7025, Ugo Basile Co.), artificial respiration was conducted under the conditions of ventilation rate of 6 ml/kg per breath and respiration rate of 90 breaths/min. The heart rate and blood pressure variations were measured with a heart rate counter (AT-601 G, Nippon Koden Co.) and a tonometer (AP-641G, Nippon Koden Co.), via a pressure transducer (DX-312, Nippon Koden Co.). After the blood pressure was stabilized, the cervical vertebrae was separated with an injection needle pricked from the occipital region. After the average blood pressure dropped to not higher than 70 mmHg, test compound (test compound-treated group) or isotonic sodium chloride solution (control group) was intravenously administered. Five (5) minutes thereafter, McNeil-A-343 (0.3 mg/kg) was intravenously administered, and whereby induced hypertension variation was recorded. In this experiment one-dose evaluation per one animal was conducted. The inhibitory effect (inhibition ratio) of the test compound on the McNeil-A-343-induced vasopressor reaction was determined by the following equation:       Inhibition    ⁢          xe2x80x83        ⁢    ratio    ⁢          xe2x80x83        ⁢          (      %      )        =            (              1        -                                                                                                  blood                    ⁢                                          xe2x80x83                                        ⁢                    pressure                    ⁢                                          xe2x80x83                                        ⁢                    variation                    ⁢                                          xe2x80x83                                        ⁢                    in                                    ⁢                                      xe2x80x83                                                                                                                                            xe2x80x83                                    ⁢                                      test                    ⁢                                          xe2x80x83                                        ⁢                    compound                    ⁢                                          -                                        ⁢                    treated                    ⁢                                          xe2x80x83                                        ⁢                    group                                                                                                                                                                blood                    ⁢                                          xe2x80x83                                        ⁢                    pressure                    ⁢                                          xe2x80x83                                        ⁢                    variation                                    ⁢                                      xe2x80x83                                                                                                                        in                  ⁢                                      xe2x80x83                                    ⁢                  control                  ⁢                                      xe2x80x83                                    ⁢                  group                                                                        )        xc3x97    100  
The 50% inhibition dose (ED50; xcexcg/kg) was calculated from the inhibition ratio of each dose of the tested compound. The results were as shown in Tables 3-1 and 3-2 as the antagonism to M1 receptor of the tested compounds.
2) Test for Antagonism to M2 Receptor (Inhibitory Effects to Acetylcholine-induced Bradycardia Reaction in Rats)
Male SD strain rats (weighing 300-500 g) were anesthetized with urethane (1 g/kg) and xcex1-chloralose (50 mg/kg) administered intraperitoneally. The airway, carotid artery and vein of each rat were isolated by laryngotomy and cannulated. The carotid artery and vein cannulae were made the routes for heart rate counting and drug administration. After suppressing the rats"" spontaneous respiration by hypodermic administration of succinylcholine (5 mg/body), artificial ventilation was conducted under the conditions of ventilation rate of 6 ml/kg per breath and respiration rate of 90 breaths/min., using a pulmotor for small animals (Model 681, Harvard Co.). The variations in heart rate and blood pressure were measured with a heart rate counter (AP-601G, Nippon Koden Co.) and a tonometer (AP-641G, Nippon Koden Co.), via a pressure transducer (DX-312, Nippon Koden Co.). After about 10 minutes"" stabilization period, heart rate change was induced by intravenous administration of acetylcholine (10 xcexcg/kg), and the mean value of the change was recorded as the value before the drug administration (pre-value) of the body. After calculating the pre-values, the test compound (test compound-treated group) or isotonic sodium chloride solution (control group) was intravenously administered. Five minutes thereafter, acetylcholine was intravenously administered and whereby induced change in the heart rate was recorded. In this experiment, one-dosage evaluation was conducted per one animal of the tested rats. The change in acetylcholine-induced bradycardia reaction (% of pre-value) caused by the test compound and isotonic sodium chloride solution was determined by the following Equation 1:       Equation    ⁢          xe2x80x83        ⁢    1    ⁢          :                  Percent      ⁢              xe2x80x83            ⁢      of      ⁢              xe2x80x83            ⁢      pre      ⁢              -            ⁢      value        =                                                                                        heart                  ⁢                                      xe2x80x83                                    ⁢                  rate                  ⁢                                      xe2x80x83                                    ⁢                  change                  ⁢                                      xe2x80x83                                    ⁢                  after                                ⁢                                  xe2x80x83                                                                                                        administration                ⁢                                  xe2x80x83                                ⁢                of                ⁢                                  xe2x80x83                                ⁢                test                ⁢                                  xe2x80x83                                ⁢                compound                                                                                        (                                  isotonic                  ⁢                                      xe2x80x83                                    ⁢                  sodium                  ⁢                                      xe2x80x83                                    ⁢                  chloride                  ⁢                                      xe2x80x83                                    ⁢                  solution                                )                                                                                                        heart                ⁢                                  xe2x80x83                                ⁢                rate                ⁢                                  xe2x80x83                                ⁢                change                ⁢                                  xe2x80x83                                ⁢                before                                                                                                          xe2x80x83                                ⁢                                  administration                  ⁢                                      xe2x80x83                                    ⁢                                      (                                          pre                      ⁢                                              -                                            ⁢                      value                                        )                                    ⁢                  of                  ⁢                                      xe2x80x83                                    ⁢                  test                  ⁢                                      xe2x80x83                                    ⁢                  compound                                                                                                        (                                  isotonic                  ⁢                                      xe2x80x83                                    ⁢                  sodium                  ⁢                                      xe2x80x83                                    ⁢                  chloride                  ⁢                                      xe2x80x83                                    ⁢                  solution                                )                                                        xc3x97      100      
The inhibitory effect (inhibition ratio) of each test compound on the acetylcholine-induced bradycardia reaction was determined according to the following Equation 2:       Equation    ⁢          xe2x80x83        ⁢    2    ⁢          :                  Inhibition      ⁢              xe2x80x83            ⁢      ration      ⁢              xe2x80x83            ⁢              (        %        )              =                  (                  1          -                                                                                          %                    ⁢                                          xe2x80x83                                        ⁢                    of                    ⁢                                          xe2x80x83                                        ⁢                    pre                    ⁢                                          -                                        ⁢                    value                                                                                                                    (                                          test                      ⁢                                              xe2x80x83                                            ⁢                      compound                      ⁢                                              -                                            ⁢                      treated                      ⁢                                              xe2x80x83                                            ⁢                      group                                        )                                                                                                                                            %                    ⁢                                          xe2x80x83                                        ⁢                    of                    ⁢                                          xe2x80x83                                        ⁢                    pre                    ⁢                                          -                                        ⁢                    value                                                                                                                    (                                          control                      ⁢                                              xe2x80x83                                            ⁢                      group                                        )                                                                                      )            xc3x97      100      
Fifty (50%) inhibition dose (ED50; xcexcg/kg) was calculated from the inhibition ratio of each dose of the tested compound. The results were as shown in Tables 3-1 and 3-2 as the antagonism to M2 receptor of tested compounds.
3) Test for Antagonism to Muscarinic M3 Receptor (Inhibitory Effects on Acetylcholine-induced Airway Resistance-increasing Reaction in Rats)
Male SD strain rats (weighing 300-500 g) were anesthetized with urethane (1 g/kg) and xcex1-chloralose (50 mg/kg) administered intraperitoneally. The airway and carotid artery of each rat were isolated by laryngotomy and cannulated. The-carotid artery cannula was used as the test compound administration route. After suppressing spontaneous respiration by hypodermic administration of succinylcholine (5 mg/body), the rats were transferred into Plethysmograph-box (PLYAN, Buxco) and artificially ventilated under the conditions of ventilation rate of 6 ml/kg per breath and respiration rate of 90 breaths/min., using a pulmotor for small animals (Model 681, Harvard Co.). Measurements of air rate and intracellular pressure, calculation of airway resistance and lung compliance and their recording were conducted with lung function analyzer (Model 6, Buxco). After about 10 minutes"" stabilization period, the change in airway resistance induced by intravenous administration of acetylcholine (50 xcexcg/kg) was measured twice at 5 minutes"" interval. The change in airway resistance induced by the second acetylcholine administration was recorded as the pre-administration of the tested rat (pre-value). Five (5) minutes after the second acetylcholine-induced reaction measurement, the test compound or isotonic sodium chloride solution was intravenously administered. Five (5) minutes thereafter, acetylcholine was administered and whereby induced airway resistance change was measured. In this experiment, one-dosage evaluation was conducted per one animal of the tested rats. The changes in acetylcholine-induced airway resistance-increasing reaction (% of pre-value) caused by the tested compound and isotonic sodium chloride solution were calculated by the following Equation 1:       Equation    ⁢          xe2x80x83        ⁢    1    ⁢          :                  Percent      ⁢              xe2x80x83            ⁢      of      ⁢              xe2x80x83            ⁢      pre      ⁢              -            ⁢      value        =                                                                      change                ⁢                                  xe2x80x83                                ⁢                in                ⁢                                  xe2x80x83                                ⁢                airway                ⁢                                  xe2x80x83                                ⁢                resistance                ⁢                                  xe2x80x83                                ⁢                after                                                                                        administration                ⁢                                  xe2x80x83                                ⁢                of                ⁢                                  xe2x80x83                                ⁢                test                ⁢                                  xe2x80x83                                ⁢                compound                                                                                        (                                  isotonic                  ⁢                                      xe2x80x83                                    ⁢                  sodium                  ⁢                                      xe2x80x83                                    ⁢                  chloride                  ⁢                                      xe2x80x83                                    ⁢                  solution                                )                                                                                                        change                ⁢                                  xe2x80x83                                ⁢                in                ⁢                                  xe2x80x83                                ⁢                airway                ⁢                                  xe2x80x83                                ⁢                resistance                ⁢                                  xe2x80x83                                ⁢                before                                                                                        administration                ⁢                                  xe2x80x83                                ⁢                of                ⁢                                  xe2x80x83                                ⁢                test                ⁢                                  xe2x80x83                                ⁢                compound                                                                                        (                                  isotonic                  ⁢                                      xe2x80x83                                    ⁢                  sodium                  ⁢                                      xe2x80x83                                    ⁢                  chloride                  ⁢                                      xe2x80x83                                    ⁢                  solution                                )                                                        xc3x97      100      
The inhibitory effect (inhibition ratio) of each test compound on the acetylcholine-induced airway resistance-increasing reaction was determined according to the following Equation 2.       Equation    ⁢          xe2x80x83        ⁢    2    ⁢          :                  Inhibition      ⁢              xe2x80x83            ⁢      ration      ⁢              xe2x80x83            ⁢              (        %        )              =                  (                  1          -                                                                                          %                    ⁢                                          xe2x80x83                                        ⁢                    of                    ⁢                                          xe2x80x83                                        ⁢                    pre                    ⁢                                          -                                        ⁢                    value                                                                                                                    (                                          test                      ⁢                                              xe2x80x83                                            ⁢                      compound                      ⁢                                              -                                            ⁢                      treated                      ⁢                                              xe2x80x83                                            ⁢                      group                                        )                                                                                                                                            %                    ⁢                                          xe2x80x83                                        ⁢                    of                    ⁢                                          xe2x80x83                                        ⁢                    pre                    ⁢                                          -                                        ⁢                    value                                                                                                                    (                                          control                      ⁢                                              xe2x80x83                                            ⁢                      group                                        )                                                                                      )            xc3x97      100      
Fifty (50)% inhibition dose (ED50; xcexcg/kg) was calculated from the inhibition ratio of each dose of the tested compound. The results were as shown in Tables 3-1 and 3-2 as the antagonism to M3 receptor of the tested compounds.
As is clear from the results as shown in above Tables 3-1 and 3-2, the compounds of the present invention exhibited high M3 selectivity also in vivo.
4) Test for Antagonism to M3 receptor (Bronchodilation in Anesthetized Dogs)
The bronchodilation action of inhaled test compound was evaluated by measuring the compounds"" inhibitory action on respiratory resistance-increasing reaction induced by a methacholine provocation test. For the experiment, 12 to 36 months old male beagle dogs (weighing 10-15 kg) were used. After being anesthetized by intravenous pentobarbital administration (30 mg/kg), the dogs were intubated cannulae in their trachea. After their respiration became stable, the cannulae were connected with Astograph (TCK-6100H, Chest) and a methacholine provocation test by 3 Hz oscillation method was conducted. The inhaling inducer, methacholine, was diluted with isotonic sodium chloride solution in 10-grade concentration levels starting from 40,000 xcexcg/ml, successively as 20,000 to 10,000, 5,000, 2500, 1250, 625, 312.5, 156 and 78 xcexcg/ml. The dogs were caused to inhale these methacholine solutions each for one minute starting from the one of low concentration with the nebulzzer in the Astograph, and changes in respiratory resistance were continuously plotted. The methacholine concentration at which the respiratory resistance increased to twice the initial value was recorded as the methacholine reaction threshold value. Before evaluating the test compounds, the methacholine reaction threshold value1) under no drug treatment was measured at least twice at a week""s interval, to select the dogs showing reproducible reaction.
The inhaling administration of each test compound (1 mg/ml) was conducted for 10 minutes under pentobarbital anesthetization (30 mg/kg, i.v.), with the nebulizer in the Astograph. Thereafter pentobarbital was additionally administered when necessary, to maintain the anesthetized condition. Four hours after the administration, a methacholine provocation test was conducted, to measure the methacholine reaction threshold value2) after administration of each test compound. The bronchodilator activity (shift value) of each tested compound was determined according to the following equation:       Shift    ⁢          xe2x80x83        ⁢    value    =                                          methacholine            ⁢                          xe2x80x83                        ⁢            reaction            ⁢                          xe2x80x83                        ⁢            threshold            ⁢                          xe2x80x83                        ⁢                          value                              1                )                                                                                      after            ⁢                          xe2x80x83                        ⁢            drug            ⁢                          xe2x80x83                        ⁢            administration                                                                    methacholine            ⁢                          xe2x80x83                        ⁢            reaction            ⁢                          xe2x80x83                        ⁢            threshold            ⁢                          xe2x80x83                        ⁢                          value                              2                )                                                                                      without            ⁢                          xe2x80x83                        ⁢            drug            ⁢                          xe2x80x83                        ⁢            administration                              
As is clearly demonstrated in above Table 4, the compounds of the present invention exhibited powerful bronchodilation action and long duration of the action.
As above, the compounds of formula [I] of the present invention exhibit potent and selective antagonistic activity against muscarinic M3 receptor. Hence, they can be administered to patients orally or parenterally as safe pharmaceutics exhibiting little side effects, for treating, in particular, such respiratory diseases as chronic obstructive pulmonary diseases, chronic bronchitis, asthma, chronic respiratory tract obstruction, fibroid lung, pulmonary emphysema and rhinitis; digestive diseases such as irritable bowel syndrome, convulsive colitis, gastroduodental ulcer, convulsion or hyperanakinesia of digestive tract, diverticulitis and pain accompanying contraction of smooth muscles of the digestive system; urinary diseases accompanied by dysuria like urinary incontinence, urgency and pollakiuria in nervous pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, cystospasm and chronic cystisis; and motion sickness.
For actual use of those compounds of the present invention for therapeutic treatment or prophylaxis of diseases as exemplified above, they may be combined with pharmaceutically acceptable adjuvants in the usual manner to formulate pharmaceutical preparations of forms suitable for administration. For this purpose, there can be used a variety of adjuvants which are commonly used in the field of pharmaceutics. Such adjuvants include, for example, gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminate metasilicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hardened castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin and hydroxypropylcyclodextrin.
The dosage forms of pharmaceutical preparations formulated using these adjuvants include solid preparations such as tablets, capsules, granules, powders and suppositories; and liquid preparations such as syrups, elixirs and injections. These preparations may be formulated according to conventional techniques well-known in the field of pharmaceutics. Liquid preparations may be in a form which is dissolved or suspended in water or other suitable medium prior to use. In particular, injections may be in the form of a solution or suspension in physiological saline solution or a glucose solution, or in powder form to be dissolved or suspended in physiological saline or a glucose solution prior to use. If desired, such injections may contain buffer agents and/or preservatives.
As preparations for oral administration, such formulation forms, besides ordinary tablets, capsules, granules, powders and the like, aerosols or dry powders for inhalation, elixiers or suspensions containing spices or coloring agents may be employed.
In these pharmaceutical preparations, a compound in accordance with the present invention may be present at a ratio of from 1.0 to 100% by weight, preferably 1.0 to 60% by weight, based on the total weight of individual preparation. These pharmaceutical preparations may additionally contain other therapeutically effective compounds.
When the compounds of the present invention are used as drugs, their dosage level and dosage schedule may vary according to the sex, age, body weight, severity of symptoms of individual patient, type and range of the desired therapeutic effect, and the like. Generally for oral administration, they are preferably administered in a daily dose of 0.1 to 100 mg/kg for adults and this daily dose may be given at a time or in several divided doses. For parenteral administration, they are preferably administered in a daily dose of 0.001 to 10 mg/kg which may be given at a time or in several divided doses.
Hereinafter the present invention is more specifically explained with reference to working examples, it being understood that the examples are in no way limitative of the scope of the invention.